1-(2-cyclohexylethyl) -6 or 7 methoxy-1,2,3,4-tetrahydroisoquinoline and acid addition salts thereof

ABSTRACT

A 6- or a 7-methoxyisoquinoline compound having the formula   WHEREIN N IS 1-3 AND ITS PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS ARE CUTANEOUS VASODILATORS. Compound (I) is produced by dehydrating an amide compound having the formula WHEREIN N IS AS DEFINED ABOVE. Compound (II) is produced by hydrogenating compound (I).

United States Pateni Yamato et al.

3,714,171 Jan. 30, 1973 METHOXY-l,2,3,4- TETRAHYDROISOQUINOLINE AND ACIDADDITION SALTS THEREOF [75] Inventors: Eisaku Yamato, Yono; Yuji Miura,V

Kawaguchi; Masao Wada, Warabi; Toshio Seki'guchi, Kawasaki; MasazurniKawanishi, Tokyo; Masanori Y Sato, Toda; Masao Hoshiy'ama, Tokyo; TakuNagao, Warabi, all of Japan [73] Assignee: Tanabe Seiyaku, Co., Ltd.,I-ligashiku,Osaka,Japan 22 Filed: J Dec. '13, 197i 7 I 21 Appl. No.:207,598

v Related U.S. Application Data [62] Division of Ser. No. 3,506, Jan.16,1970, abandoned.

[30] Foreign Application Priority Data Jan. 25, 1969 v Japan. ....4 45490 Jan. 25, 1969 Japan ...44/5491 [52] U.S. Cl. .....260/286 R,260/283 SY, 260/289 R, 260/557 R, 424/258 [51] Int. Cl...'....-..C070'35/10 [58] Field of Search ..260/289, 289 A, 286 R [56]References Cited UNITED STATES PATENTS 3,644,366 2/1972 Seanmart..260/286 R 2,633,709 12/1953 Craig ..260/286 R 2,683,146 7/1954Robinson ..260/286 R 1-(2-CYCLOHEXYLETHYL),-6 OR 7 OTHER PUBLICATIONSBattersby et al., Chem. Abstr. V01. 56, col.

CHaO

H2)n H (11) wherein n is 1-3 and its pharmaceutically acceptable acidaddition salts are cutaneous vasodilators. Compound (1) is produced bydehydrating an amide compound having the formula O OH: I NH (CH2)nwherein n is as defined above.

Compound (ll) is produced by hydrogenating compound (l).

3 Claims, No Drawings (III) I-(Z-CYCLOHEXYLETHYL) -6 R 7 METHOXY-1,2,3,4-TETRAHYDROISOQUINOLINE AND ACID ADDITION SALTS THEREOF This is adivision of application Ser. No. 3,506, filed Jan. 16, 1970 and nowabandoned.

This invention relates to novel derivatives of 6- or 7-methoxyisoquinoline and to a process for preparing same.

The derivatives of the present represented by the following formulae:

wherein n is an integer from 1 to 3. Pharmaceutically acceptable acidaddition salts of these derivatives are also included within the scopeof the instant invention.

We have found that the above mentioned new derivatives of 6- or7-methoxyisoquinoline and their acid addition salts are useful ascutaneous vasodilators. The cutaneous vasodilating action of compounds(I) or (II) of this invention is estimated to be about 2 to timesstronger than that of papaverine. The compounds of the present inventionare characterized by their selective action on cutaneous blood vessels.Moreover, the compounds of the present invention do not show thisdilating action on any other peripheral blood vessels. For example, thefollowing compounds increased the flow rate of blood in the auricularblood vessel of the rabbit (body weight 4.0-4.5 kg.) about 4 to 5 timesgreater than did papaverine when said compounds were administered intosaid vessel respectively at a dose of 5 g/ear;l-(3-cyclo-hexylpropyl)-6-methoxy-3,4-dihydroisoquinoline(hydrochloride)zl-cyclohexylmethyl-6methoxy-1,2,3,4-tetrahydroisoquinoline(hydrochloride): 1 2-cyclohexylethyl)-7methoxy- 1,2,3,4-tetrahydroisoquinoline(hydrochloride): cyclohexylpropyl)-6-methoxy-l,2,3 ,4- tetrahydroisoquinoline(hydrochloride). It should be noted thatthese compounds showed no such dilating effect on the common carotidartery of dogs.

The toxicity of the isoquinoline compounds (I) and (11) is relativelylow. For example, the acute toxicity (LD of1-(3-cyclohexylpropyl)-6-methoxy- 3,4dihydroisoquinoline hydrochloridewhen ministered to mice intravenously is about 55 mg./kg.

According to this invention, the isoquinoline compounds (I) and (II) canbe prepared by dehydrating an amide compound represented by theformulae:

invention are CHaO (III) stituted 6- or7-methoxy-3,4-dihydroisoquinoline compound which can be furtherhydrogenated to produce the compound (II).

The above stated processes may be represented by the following reactionscheme:

(A) CHaO l R NH The starting compound (III) is readily obtainable. Forexample, it may be produced by heating 3- or 4- methoxy phenethylaminefor a few hours in an oil bath, with an acid represented by the formula:

wherein n is as defined above.

The dehydration reaction of the present invention can be carried out byheating the compound (III) in the presence of dehydrating agent (e.g.phosphorus oxychloride, phosphorus pentachloride, polyphosphoric acid oresters of polyphosphoric acid). Suitable reaction solvents include, forexample, benzene, toluene, xylene, chloroform, carbon tetrachloride,etc. It is, however, not essential to use said solvents in carrying outthe reaction. When phosphorus oxychloride is employed as the dehydratingagent, it may also serve as the reaction solvent.

l-substituted-6- or 7methoxy-l ,2,3 ,4- tetrahydroisquinoline (II) canbe prepared by hydrogenating the corresponding 3,4-dihydroisoquinoline(l). The hydrogenation reaction may be effected by an appropriateprocedure. For example, a chemical hydrogenation using an agent such assodium borohydride, zinc-acetic acid, zinc-hydrochloric acid orironhydrochloric acid may be employed. Alternatively, a catalytichydrogenation using a catalyst such as Raney-nickel, paladium-carbon orAdams platinum may be used. Methanol, ethanol, tetrahydrofuran, aqueousmethanol, etc., are suitable reaction solvents.

The isoquinoline compounds (1) and/or (11) can be employed forpharmaceutical use either as the free base or a salt thereof. The baseand salt thereof are readily convertible from one to the other byconventional manner. Examples of preferred therapeutically acceptablesalts are salts formed with mineral acids, such as hydrochloric acid,hydrobromic acid, perchloric acid, nitric acid, sulfuric acid orphosphoric acid, or with organic acids such as formic acid, acetic acid,

dehydration propionic acid, glycollic acid, lactic acid, pyruvic acid,oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid,malic acid, citric acid, tartaric acid, ascorbic acid, hydroxymaleicacid, benzoic acid, phenylacetic acid, aminobenzoic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,ptoluenesulfonic acid, sulfanilic acid, aspartic acid or glutamic acid.The isoquinoline compounds (1) and/or (11) may be used in pharmaceuticalpreparations in conjunction or admixture with a pharmaceutical excipientthat is suitable for enteral or parenteral administration. The excipientselected should be one that does not react with the isoquinolinecompounds (I) and/or (11). Suitable excipients include, For example,

gelatin, lactose, glucose, sodium chloride, starch, mag- EXAMPLE 1 1. Amixture of 4.1 g. of 3-methoxyphenethylamine and 4.0 g. ofcyclohexylacetic acid is heated for 3.5 hours in an oil bath at atemperature of l80l90C., and the resulting water is removed bydistillation. The mixture is allowed to cool and is then dissolved inbenzene. The resultant benzene solution is then successively washed withpercent hydrochloric acid, water, 10 percent sodium hydroxide and water.The solution is then dried and evaporated to remove the solvent. Theresidue thus obtained'is recrystallized from a mixture of benzene andn-hexane. 6.28 g. of N-(B-methoxyphenethyl)-2-cyclohexyl acetamide areobtained. M.p. 74.5-75.5C. Colorless needles. Yield: 84.1 percentvAnalysis calculated for C,,H, O N

C,74.14: H,9.l5: N,5.09

Found: C,74.43: 11,9.38: N,5.11

2. A mixture of 6.0 g. of N-(3-methoxyphenethyl)- 2cyclohexylacetamide,30 ml. of absolute benzene and 7 ml. of phosphorus oxychloride isrefluxed for 2 hours. The reaction mixture is then evaporated underreduced pressure to remove the solvent. The residue thus obtained ismixed with ice-water to decompose the remaining phosphorus oxychloride,and the resultant mixture is washed with benzene. The aqueous layer isalkalinized with sodium bicarbonate and the resulting oil is extractedwith benzene. The benzene layer is washed with water, dried andevaporated to remove the solvent. The residue is then distilled underreduced pressure. 5.04 g. of l-cyclohexylamethyl-6-methoxy-3,4-dihydroisoquinoline boiling at 170-176C/2 mmHg. are obtained.Colorless viscous oil. Yield: 90 percent Hydrochloride (recrystallizedfrom methanolether) M.p. l95-l96.5C. (decomp.) Colorless prisms.

. Analysis calculated for C H ON HCl C,69.50: H,8.24: N,4.76: Cl,l2.06Found: C,69.52: H,8.25: N,4.72: Cl,l2.0l

EXAMPLE 2 16.8 g. of N-(3-methoxyphenethyl)-3-cyclohexylpropionamide areobtained in the same manner as is described in Example l-(l) exceptingthat 10.3 g. of cyclohexylpropionic acid are used instead ofcyclohexylacetic acid. M.p. 606l.5C. Colorless needles (recrystallizedfrom benzene). Yield: 87.7 percent Analysis calculated for c ii omC,74.70: H,9.40: N,4.84

Found: C,74.9l: H,9.54: N,4.82

16 g. of l-(2-cyclohexylethyl)-4-methoxy-3,4- dihydroisoquinolinehydrochloride are obtained in the same manner as is described in Example1 (2) excepting that 16.5 g. ofN-(3-methoxyphenethyl)-3-cyclohexylpropionamide are used instead ofN-(B-methoxyphenethyl)-2-cyclohexylacetamide. M.p. 173l 74C. (decomp.)Colorless needles (recrystallized from isopropanol-ether) Yield: 91.5percent Analysis calculated for C ll ON HCl Found: C,70.07: H,8.60:N,4.54: C1,l 1.34

EXAMPLE 3 17.3 g. of N-(3-methoxyphenethyl)-4-cyclohexylbutyrylamide areobtained in the same manner as is described in Example l-(l) exceptingthat 10 g. of cyclohexylbutyric acid are used instead ofcyclohexylacetic acid. B.p. 200-203C/0.6 mmHg. Colorless oil. Yield:96.6 percent Analysis calculated for C,,H,,0,N

Found: C,75.34: H,9.78: N,4.64

14.3 g. of l-(3-cyclohexylpropyl)-4-methoxy-3,4- dihydroisoquinolinehydrochloride are obtained in the same manner as is described in ExampleI-(2) excepting that 16.9 g. of N-(3-methoxyphenethyl)-4-cyclohexylbutryrlamide are used instead of N-(3-methoxyphenethyl)-2-cyclohexylacetamide. M.p. 58C. Colorless needles(recrystallized from acetonewater-ether). Yield: 79.9 percent Analysiscalculated for C H ON HCl C,68.97: H,8.84: N,4.23: Cl,10.72

Found: C,68.90: H,8.86: N,4.23: Cl,l0.70

EXAMPLE 4 5.07 g. of 1-cyclohexylmethyl-6-methoxy-3,4-dihydroisoquinoline hydrochloride are dissolved in 40 ml. of methanol.0.7 g. of sodium borohydride is gradually added to the solution over aperiod of about 20 minutes while cooling at a temperature of about 10C.After a standing period of 30 minutes at room temperature, the solutionis refluxed for 30 minutes. The reaction solution is then evaporated toremove solvent. The residue thus obtained is mixed with 10 percentsodium hydroxide and diluted with water. The resultant solution isextracted with benzene. The benzene layer is washed with water, driedand evaporated to remove the solvent and the residue is distilled underreduced pressure. 4.34 g. of l-cyclohexyl-methyl-6-methoxy-l ,2,3,4-tetrahydroisoquinoline boiling at 1751 80C/2 mmHg. are obtained.Colorless viscous oil. Yield: 96.8 percent. The hydrochloride salt ofthis compound is recrystallized from a mixture of methanol and ether togive colorless needles melting at 206208C.

Analysis calculated for C H 'ON HCl C,69.01: 11,8.86: N,4.73:Cl,11.99Found: C,69.06: 11,9.00: N,4.77: Cl,1 1.99

EXAMPLE 5 6.81 g. of 1-(2-cyclohexylethyl)-6'methoxy-l,2,3,4-tetrahydroisoquinoline hydrochloride are obtained in the same manner asis described in Example 4 excepting that 8 g. of1-(2-cyc1ohexylethyl)-6-methoxy-3,4- dihydroiso-quinoline hydrochlorideare used instead of 1-cyclohexylmethyl-6-methoxy-3,4-dihydroisoquinoline hydrochloride. M.p. 227229C. Colorless needles(recrystallized from methanol-ether). Yield: 84.5 percent.

Analysis calculated for C ,l-l ON HCl C,69,76:H,9.10:N,4.52:Cl,11.44

Found C,69.82:H,9.34:N,4.55:Cl,l1.61

EXAMPLE 6 7.4 g. of 1-(3-cyclohexylpropyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride are obtained in the same manner asis described in Example 4 excepting that 8.2 g. of1-(3-cyclohexylpropyl)-6-methoxy- 3,4-dihydroisoquinoline hydrochlorideare used instead of 1-cyclohexylmethyl-6-methoxy-3,4-dihydroisoquinilinehydrochloride. M.p. 167-l69C. Colorless needles (recrystallized frommethanol-ether). Yield: 90.4 percent Analysis calculated for C H ON HClC,70.46: H,9.33: N,4.32: Cl,l0.94

Found:C,70.51:1-1,9.36:N,4.31:C1,10.90

EXAMPLE 7 1. A mixture of 7.5 g. of 4-methoxy-phenethylamine and 7.0 g.of cyclohexylacetic acid is heated for 2.5 hours in an oil bath at atemperature of 180190C, and the resulting water is removed bydistillation. The mixture is allowed to cool and is then dissolved inchloroform. The chloroform solution is successively washed with 10percent hydrochloric acid, water, 10 percent sodium hydroxide and water.The solution is dried and evaporated to remove the solvent. The residuethus obtained is recrystallized from a mixture of benzene and n-hexane.11.9 g. of N-(4-methoxyphenethyl)-2-cyclohexyl-acetamide are obtained.M.p. 109-110C. Colorless needles. Yield: 87.1 percent Analysiscalculated for C H 0 N C ,74.l4: H,9.15: N,5.09

Found: C,74.59: H,9.29: N,5.12

2. A mixture of l 1 g. of N-(4-methoxyphenethyl) 2- cyclohexylacetamide,33 g. of phosphorus pentoxide, g. of sellaite and 200 ml. of absolutebenzene is stirred vigorously and refluxed for 8 hours. The reactionmixture is allowed to cool. It is then poured into ice-water todecompose the remaining phosphorus pentoxide. 20 ml. of 35 percenthydrochloric acid are added to the solution. The solution is then heatedto 80C. After cooling, the insoluble materials are removed byfiltration, and the aqueous layer is separated from the filtrate andwashed with benzene, alkalinized with 20. percent sodium hydroxide andextracted with ether. The ether layer is washed with an aqueous solutionsaturated with sodium chloride. The solution is then dried andevaporated to remove the solvent and the resultant residue is distilledunder reduced pressure. 3.6 g. of 1-cyclohexylmethyl-7-methoxy-3,4-dihydroisoquinoline boiling at l62-l64C/2 mml-lg. are obtained. Slightlyyellow oil. Yield: percent Hydrochloride (recrystallized from ethanolether) M.p. l92l 93C. (decomp.) Colorless needles.

Analysis calculated for C I- ON HCl C,69.50: 118.24: N,4.76: Cl,12.06Found: C,69.24: H,8.3 l N,4.86: Cl,l2.52

EXAMPIIE? W 7 24.87 g. .ofN-(4-methoxyphenethyl)-3-cyclohexylpropionamide are obtained in the samemanner as is described in Example 7-(1) excepting that 15.6 g. ofcyclohexylpropionic acid are used instead of cyclohexylacetic acid. M.p.l 1 1C. Colorless needles (recrystallized from benzene-n-hexane). Yield:86.0 percent Analysis calculated for C H ,O N

C,74.70: H,9.40: N,4.84

Found: C,75.05: H,9.53: N,4.77

2.45 g. of 1-(2-cyclohexylethyl)-7-methoxy-3,4- dihydroisoquinolinehydrochloride are obtained in the same manner as is described in Example7-(2) excepting that 13 g. ofN-(4-methoxyphenethyl)'-3-cyclohexylpropionamide are used instead ofN'-(4-methoxyphenethyl)-2-cyclohexylacetamide. M.p. l68l 70C. (decomp.)Colorless prisms (recrystallized from ethanol-ether). Yield. 17.6percent Analysis calculated for C H ON HCl C,70.23:H,8.51:N,4.55:C1,l1.52 Found: C,70.16: 11,8.57: N,4.53: Cl,1 1.42

EXAMPLE 9 17.2 g. of N-(4-methoxyphenethyl)-4-cyclohexylbutyrylamide areobtained in the same manner as is described in Example 7-(1) exceptingthat 10 g. of cyclohexylbutyric acid are used instead ofcyclohexylacetic acid. M.p. 7778C. Colorless needles (recrystallizedfrom benzene-n-hexane). Yield 96.3 percent Analysis calculated for C H ON C,75.20: H,9.63: N,4.62

Found: C,74.80: H,9.71: N,4.62

1.47 g. of l.-(3-cyclohexylpropyl)-7-methoxy-3,4- dihydroisoquinolinepic rate are obtained in the same manner as is described in Example7-(2) excepting that 6 g. ofN-(4-methoxyphenethyl)-4-cyclohexylbutyrylamide are used instead ofN-(4-methoxyphenethyl)-2- cyclohexylacetamide. M.p. 149-151C. Yellowprisms (recrystallized from ethanol). Yield: 14.2 percent Analysiscalculated for C, H -,ON G l-1 0 M,

C,58.36:l-1,5.88:N,10.89

Found: C,58.84: 11,5.88: N,10.87

EXAMPLE 10 4.0 g. of 1cyclohexylmethyl-7-methoxy-3,4-dihydroisoquinoline hydrochloride are dissolved in 50 ml. of methanol.06 g. of sodium borohydride is gradually added to the solution over aperiod of about 20 minutes while cooling at a temperature of about 10C.The solution is'allowed to stand at room temperature for 30 minutes. Itis then refluxed for 30 minutes. The reaction solution is evaporated toremove the solvent. The residue thus obtained is mixed with 10 percentsodium hydroxide and diluted with water. The solution is extracted withbenzene. The benzene layer is washed with water, dried and evaporated toremove the solvent. 3.3 g. of 1-cyclo-hexylmethyl-7-methoxy-1,2,3,4-tetrahydroisoquiniline are obtained. Pale yellow oil. Thehydrochloride salt of this compound is recrystallized from a mixture ofethanol and isopropyl ether. 3.0 g. of colorless needles melting at188-l91 C. are obtained. Yield: 74.5 percent Analysis calculated for CI- ON HCl C,69.0l:H,8.86:N,4.73:C1,11.99

Found: C,69.23: l-l,9.0l: N,4.64: Cl,1 1.92

EXAMPLE 1 l 0.61 g. of 1-(2-cyclohexylethyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride is obtained in the same manner asis described in Example 10 excepting that 1.15 g. of1-(2-cyclohexylethyl)-7-methoxy-3,4- dihydroisoquinoline hydrochlorideare used instead of 1cyc1ohexylmethy1-7 -m ethoxy-3,4-dihydroisoquinoline hydrochloride.

M.p. 227-229C. Colorless needles (recrystallized from ethanol-etherYield: 52.5 percent methoxy-3,4-dihydroisoquinoline hydrochloride areAnalysis calculated for C I- ON l-lCl C,69.76:1-l,9.l0: N,4.52: Cl,11.44 Found: C,69.39: H,9.14: N,4.53: Cl,l 1.65

EXAMPLE 12 3.85 g. of 1-(3-cyclohexylpropyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride are obtained in the samemanner as is described in Example 10 excepting that 7.8 g. of1-(3-cyclohexylpropyl)-7- used instead ofl-cyclohexylmethyl-7-methoxy-3,4-

-dihydroisoquinoline hydrochloride. M .p.

1. 1-(2-Cyclohexylethyl)-6- or 7-methoxy-1, 2, 3,4-tetrahydroisoquinoline or a pharmaceutically acceptable acid additionsalt thereof.
 2. The compound as claimed in claim 1, wherein said saltis a pharmaceutically acceptable hydrohalide of1-(2-cyclohexylethyl)-6-methoxy-1, 2, 3, 4-tetrahydroisoquinoline.